Director
Edwin L. Steele Laboratory for Tumor Biology
Department of Radiation Oncology
Massachusetts General Hospital

617-726-4083

Revealing the Inner Workings of Solid Tumors
A solid tumor is an organ composed of neoplastic cells and host stromal cells, which are nourished by the vasculature and embedded in an extracellular matrix. In addition to the endothelial cells that make up the vasculature, the tumor stroma contains fibroblasts, myofibroblasts, pericytes, and cellular components of the immune system (such as macrophages).

In many human tumors, stromal cells greatly outnumber the neoplastic cells and exert a strong influence on their behavior. The interaction among these cells, the surrounding matrix, and the local cellular microenvironment influences the expression of certain genes, whose products control the pathophysiological characteristics of the tumor, govern tumor progression, and affect the tumor's response to various therapies. The over arching goal of our research is to dissect the pathophysiology of the vascular and extra-vascular components of tumors, to determine the role of tumor-host interactions in tumor biology, and ultimately to translate this knowledge into improved cancer detection, prevention, and treatment in humans.

To unravel the complex biology of tumors, we have developed an array of optical technologies, mathematical models, and sophisticated animal preparations. These include genetically engineered mice with surgically implanted transparent windows, which permit the in vivo visualization of gene expression and function in tumors and their surrounding host stroma. This undertaking has provided unprecedented molecular, cellular, anatomical, and functional insights.

Our laboratory has found that high interstitial pressure is a universal characteristic of solid tumors, and that it can compromise blood flow and impair the delivery of molecular medicine within tumors. We have identified the mechanisms underlying this elevated pressure: high vascular permeability, lack of functional lymphatics, and mechanical stress generated by tumor growth. Overexpression of the lymphangiogenic factor VEGF-C increases lymph node metastasis, but does not increase lymphatic function or decrease the interstitial pressure. However, judicious application of antiangiogenic agents can lower the pressure and improve the delivery and efficacy of various cancer treatments. To gain a deeper insight into interstitial barriers, we measured interstitial convection, diffusion, and binding using photobleaching, and pO2 and pH profiles around individual tumor vessels using phosphorescence quenching and ratio imaging. We recently proposed the novel hypothesis that the anomalous assembly of the collagen network can prevent the penetration of therapeutic agents in tumors, and showed that the hormone relaxin can modify collagen structure and improve drug diffusion.

Our finding that angiogenic molecules regulate adhesion molecules on the vasculature provided the first link between the disparate fields of angiogenesis and adhesion, and revealed a novel mechanism by which tumors evade immune recognition. In collaboration with Dr. Brian Seed, we have also discovered that cancer cells co-opt the host stromal cells and encourage them to produce pro- and anti-angiogenic growth factors. By revealing that host cells are not passive bystanders, but active participants in tumor angiogenesis, growth, metastasis, and therapeutic response, our laboratory provided a rationale for combining Herceptin with VEGF blockade for the treatment of breast cancer -a concept that led to a clinical trial.

Our work has revealed that the malfunction of the vascular and extravascular compartments in solid tumors often thwarts the effectiveness of both conventional and novel therapies. Based on our recent experimental findings, we have proposed the new hypothesis that antiangiogenic therapy can "normalize" the abnormal tumor vasculature and improve both the delivery and efficacy of therapeutics. We are currently testing this concept in a clinical trial.

By integrating principles from physiology, pharmacology, immunology, and molecular biology, our laboratory has developed mathematical models of drug delivery and pathophysiological processes in solid tumors. These modeling tools have allowed us to extract simple, important principles that should spark the development of novel diagnostic and therapeutic strategies.

Selected Publications:
Jain RK, et al . Dissecting tumor pathophysiology using intravital microscopy. Nat Rev Cancer 2002; 2:266-276.

Padera TP, et al . Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002; 296:1883 1886.

Izumi Y, et al . Herceptin acts as an anti-angiogenic cocktail. Nature 2002; 416: 279-280.

Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 2001; 7:987-989.

Fukumura D, et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94:715-725.